Review 10.4172/Neuropsychiatry.1000525 © 2018 p- ISSN 1758-2008 e- ISSN 1758-2016 Neuropsychiatry (London) (2018) 8(6), 1831–1838 1831 Advances and Challenges in Assessing 2-Hydroxyglutarate in Gliomas by Magnetic Resonance Spectroscopy: A Short Review Manabu Natsumeda 1 , Hironaka Igarashi 1 , Kunio Motohashi 1 , Yuji Suzuki 1 , Masaki Ohkubo 2 , Kouichirou Okamoto 1 , Masaki Watanabe 2 , Tsutomu Nakada 2 , Yukihiko Fujii 1,† 1 Department of Neurosurgery and Center for Integrated Brain Sciences, Brain Research Institute, University of Niigata, Niigata, Japan 2 Radiological Technology, School of Health Science Faculty of Medicine, University of Niigata, Niigata, Japan † Author for correspondence: Yukihiko Fujii, MD, PhD, Professor, Department of Neurosurgery, Brain Research Institute, University of Niigata, Niigata, Japan, Tel: 025-227-0653; email: yfujii@bri.niigata-u.ac.jp ABSTRACT The metabolite 2-hydroxyglutarate (2HG) accumulates in isocitrate dehydrogenase (IDH)- mutant gliomas and high-levels of 2HG can be non-invasively detected in living human brain by magnetic resonance spectroscopy (MRS). The concept of being able to detect a metabolite associated with an important gene mutation has generated considerable excitement in the felds of neurooncology and neuroradiology. However, challenges remain in reliably detecting 2HG before we can use it as a tool for making clinical decisions. In this review, we outline the advances and challenges in assessing 2HG by MRS. Keywords: 2-Hydroxyglutarate, Gliomas, Magnetic Resonance Spectroscopy Introduction A groundbreaking study showed isocitrate dehydrogenase (IDH) mutations in about 10% of glioblastomas [1], and subsequent studies showed IDH mutations to occur in 50-80% of astrocytomas, oligodendrogliomas, and secondary glioblastomas [2-5]. Te current understanding is that IDH mutations occur frequently, early in the cascade of astrocytomas and oligodendrogliomas [3], and is deeply involved in gliomagenesis. IDH mutations are known to be a powerful positive prognostic factor in World Health Organization (WHO) grade 3 and 4 [6,7]. IDH mutations in gliomas give rise to the metabolite 2-hydroxyglutarate (2HG) [8], which can be detected by magnetic resonance spectroscopy (MRS).  Functions of IDH and 2HG Te family of IDH enzymes includes three isoforms: IDH1, which is located in the cytoplasm, and IDH2 and IDH3, which localize in mitochondria (Figure 1). IDH3, which uses the cofactor NAD + (as opposed to NADP + for IDH1 and IDH2) as the electron acceptor, converts isocitrate to α-ketoglutarate (α-KG) as part of the tricarboxylic acid (TCA) cycle. IDH mutation is a gain-of-function mutation, in which 2HG is produced from α-KG (Figure 1) [9]. At least 5 point mutations of IDH1 and 3 point mutations of IDH2 have been reported in gliomas; IDH3 mutation has not been reported in gliomas. Te most commonly occurring point mutation in gliomas is IDH1 R132H with a frequency of 85-95% [7,10], causing a missense mutation from Arginine (R) to histidine (H). 2HG is structurally similar to α-KG and acts as a competitive antagonist, causing inhibition of α-KG-dependent dioxygenases. Tese include the JmjC domain-containing histone demethylases